APPLICANT'S ABSTRACT: Alcohol has been known to have a suppressive effect on the immune system, including alteration in the T-lymphocyte function. Although there are epidemiologic evidences to suggest that alcohol may be a risk factor in HIV transmission and cause rapid progression to AIDS, a detailed molecular mechanism is not known. Our long-range goal is to develop a therapeutic target to either eradicate or suppress HIV- 1 latency in asymptomatic patients who abuse alcohol. The objective of this application is to examine the effect of alcohol on viral infection and replication in quiescent and latent T-lymphocytes. The central hypothesis, which is based on solid Preliminary Results, is that (1) alcohol enhances viral entry by up-regulating CXCR4 chemokine co-receptor on quiescent T-lymphocytes and (2) alcohol/alpha-CD3 co-stimulation optimizes viral replication in latent T-lymphocytes. The two specific aims are to determine whether (1) CAMP/PKA pathway is involved in CXCR4 up-regulation induced by alcohol and (2) NFkB pathway is involved in alcohol/alpha-CD3 co-stimulation of viral synthesis. The approach will be to utilize specific cAMP/PKA inhibitors to examine CXCR4 trafficking, adenylate cyclase activity and LTR transcription regulation. We will also study the effect of alcohol on cell cycle and the involvement of NFkB by examining gene transcription and the upstream regulatory events. The proposed work is innovative, because although the causal relationship between alcohol and HIV infection has been documented in epidemiological studies, a direct effect of alcohol on latent/quiescent T-lymphocytes has not been demonstrated until now. It is our expectation that these studies will identify the signal transduction cascade and the regulation of the genes involved in alcohol related HIV infection and replication. These results will be significant because they provide a novel target site for designing pharmaceutical product to suppress reactivation of viral latent T-lymphocyte in HIV patient with history of alcohol abuse. In addition, by confirming the potential risk of alcohol in HIV infection and/or progression from chronic infection to full-blown AIDS, we can implement a social program to educate the public about the risk of alcohol and unprotected sex, especially in the minority population. Furthermore, these results will fundamentally advance the field of alcohol and HIV pathogenesis.